FR2655042A1 - NOVEL SUBSTITUTED BENZOTHIAZOLINONES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. - Google Patents

Abstract

Compounds of general formula (I): (I) in which: R1 represents a hydrogen atom or a lower alkyl group, and R2 represents a substituted or unsubstituted alkyl, a phenyl or a substituted or unsubstituted heteroaryl, their enantiomers, diastereoisomers and epimers and their addition salts with a pharmaceutically acceptable base when R1 represents a hydrogen atom or when R2 comprises a carboxylic acid group. Medicinal products.

Description

1 - The present invention relates to new benzothiazolinones

  substituted, their preparations and pharmaceutical compositions which

contain them.

  Many benzothiazolinone derivatives have been described in therapy as having a wide variety of pharmacological properties. Patent JP 86143307 describes in particular 6-alkylbenzothiazolinones as fungicides; JP 85130574 discloses 6-amido benzothiazolinones as cardiac stimulants; Finally, patent WO 850 1289 describes inter alia 6-acyl benzothiazolinones in

as anti-inflammatory.

  Patents FR 7323280 and FR 8020861 describe, for their part, acyl-

  6 benzoxazolinones useful as analgesics.

  The applicant has now discovered benzothiazolinone derivatives endowed with an analgesic activity of a level which is much more interesting than that of the derivatives described in the patent.

FR 7323280.

  In addition, the derivatives of the invention possess the characteristic

  particularly advantageous to be totally devoid of anti-activity.

  In this respect, the compounds of the present invention are endowed with a high level of pure analgesic activity. However, most of the non-morphine analgesic substances known to date also possess a high level of analgesic activity. 2- anti-inflammatory activity (examples: salicylates, pyrazoles) and they therefore affect the processes of inflammation These involve a large number of chemical mediators (prostaglandins, thromboxane A 2); this results in multiple side effects, the best known of which are: gastric mucosal attack with the possibility of ulcers, inhibition of platelet aggregation with coagulation disorders In addition to the disturbances they cause, these parallel effects prevent The use of these products in many subjects who are particularly sensitive thereto. Being devoid of any anti-inflammatory activity, the compounds of the present invention therefore do not interfere with the mediators of inflammation and are therefore free from the side effects mentioned. This feature, together with their complete lack of toxicity and high level of activity, makes the compounds of the present invention usable as analgesic in a much safer way and without the restrictions of use.

  usually known for the vast majority of these products.

  The products of the invention also possess antiplatelet platelet activity and could be used in prevention.

arterial accidents.

  More specifically, the invention relates to the derivatives of general formula (I) R 1 R 1

S CH 2 R 2

  in which R1 represents a hydrogen atom or a lower alkyl group, R 2 represents: a linear or branched lower alkyl group optionally substituted by one or more halogen atoms or by one or more alkoxy, hydroxyl or phenyl groups; , carboxylic acid, or cyano, provided that if R1 represents a hydrogen atom then R 2 can not represent a methyl group or a methyl group substituted with a halogen atom, * an aryl group optionally substituted with one or several: halogen atoms, or cyano groups, lower alkyl groups optionally substituted with one or more halogen atoms, or lower alkoxy groups, or carboxylic acid or hydroxy, a heteroaryl group preferably 2-thienyl, 2-furyl optionally substituted by a linear or branched lower alkyl group, the lower term indicating that the groups so qualified They contain 1 to 6 carbon atoms, their enantiomers, diastereoisomers and epimers, and when R 1 represents a hydrogen atom or when R 2 comprises a carboxylic acid group, their addition salts with a pharmaceutically acceptable base.

acceptable.

  Among the bases that can be added to the compounds of formula (I) for which R 1 represents a hydrogen atom or when R 2 comprises a carboxylic acid group, there may be mentioned, by way of example, sodium hydroxides , potassium, calcium or organic bases such as -4-diethylamine, diethanolamine, triethylamine, benzylamine, dicyclohexylamine, arginine, or alkali metal carbonates or

alkaline earthy.

  The invention also extends to the process for obtaining compounds of general formula (I), characterized in that a derivative of formula (II) is used as raw material: R 1 I (II) oo O described in patent application FR 89 05655, in which R 1 and R 2 have the same meaning as in formula (I), which, in an acid medium, are reduced by a trialkylsilane according to the method of CT WEST and Coll (J Org Chem 1973, 38, (15), 2675-2681) to conduct after purification by a technique chosen from washing, chromatography and / or crystallization with the product of formula (I): R 1 I o O (I)

CH 2 R 2

  which, when R 2 comprises a cyano group can be converted into a derivative of formula (I) wherein R 2 comprises a carboxylic group by action on the derivative of formula (I / A) previously obtained from a strong acid, which when R 2 comprises a halogen atom can be treated with an alkali metal cyanide to give a derivative of formula (I / A) wherein R 2 comprises a cyano group, which cyano group can be converted into a group t

C, _- R 2

  it is carboxylated as indicated above to give a derivative of formula (I) in which R 2 comprises a carboxylic acid group, from which the isomers are optionally separated by a conventional separation technique and which is salified, if desired, when R1 represents a hydrogen atom or when R 2 comprises a carboxylic acid group

  by a pharmaceutically acceptable base.

  The compounds of formula (I) possess properties

interesting pharmacological

  The pharmacological study of the derivatives of the invention has in fact shown that they are not very toxic, endowed with a high level of analgesic activity and devoid of anti-inflammatory activity. This spectrum of activity thus renders the compounds of the present invention. interesting in a number of indications such as rheumatoid arthritis, neuralgia, lumbosciatic, cervico-brachial neuralgia, pain

  traumas such as sprains, fractures, dislocations, post-traumatic pain

  traumatic, postoperative pain, dental pain, neurological pain such as facial neuralgia, visceral pain such as renal colic, dysmenorrhea, proctologic surgery, pain of the sphere O R L, pancreatitis, various pain, headache,

cancer pain.

  The subject of the present invention is also the pharmaceutical compositions containing the products of formula (I) or one of their addition salts with a pharmaceutically acceptable base, alone or in combination with one or more inert excipients or carriers.

  toxic, pharmaceutically acceptable.

  Among the pharmaceutical compositions according to the invention, mention may be made more particularly of those which are suitable for oral, parenteral, nasal administration, single or sugar-coated tablets, sublingual tablets, sachets, packets, capsules, glossettes, tablets, suppositories, creams, ointments, dermal gels, etc.

-6 2655042

  The useful dosage varies according to the age and weight of the patient, the route of administration, the nature of the therapeutic indication or any associated treatments and ranges from 1 centigram to

4 grams per 24 hours.

  The following examples illustrate the invention and do not limit it in

no way.

  EXAMPLE 1 BENZYL-6 BENZOTHIAZOLINONE

  In a 150 cm 3 flask, weigh 10.2 g (0.04 mol) of 6-benzoyl benzothiazolinone. Add 45.6 g (0.4 mole) of trifluoroacetic acid

  via a dropping funnel with a teflon valve.

  Add, under magnetic stirring, dropwise and while cooling with a tray of ice water 10.5 g (0.09 mole) of triethylsilane Adapt a calcium chloride guard and continue stirring for fifteen hours at the ambient temperature pour, with stirring, the reaction mixture into 500 cm 3 of ice water.

  precipitate obtained, wash with water until the washing water is neutral.

  Dry and recrystallize in toluene.

  Yield: 95% Melting point: 140-142 ° C. Elemental microanalysis: Caleulée C: 69.68 H: 4.59 N: 5.80 Found C: 69.67 H: 4.46 N: 5.80

  EXAMPLE 2: 3-METHYL BENZYL-6 BENZOTHIAZOLINONE

  Proceed in the same way as in example 1, replacing the

  benzoyl-6 benzothiazolinone by 3-methyl-6-benzoyl benzothiazolinone.

Recrystallize in ethanol.

  Yield: 94% Melting Point: 114-115 Elemental Microanalysis: Calculated C: 70.55 H: 5.13 N: 5.48 Found C: 69.99 H: 5.18 N: 5.47

  EXAMPLE 3 (CHLORO-4 BENZYL) -6 BENZOTHIAZOLINONE

  Proceed in the same way as in example 1, replacing the

  benzoyl-6 benzothiazolinone by (4-chlorobenzoyl) benzothiazolinone.

  Recrystallize in acetonitrile.

  Yield: 90% Melting point: 174-176 ° C

  EXAMPLE 4: METHYL-3 (CHLORO-4 BENZYL) 6 BENZOTHIAZOLINONE

  Proceed in the same manner as in Example 1, replacing the 6-benzoyl benzothiazolinone by methyl-3 (4-chlorobenzoyl) -6

  benzothiazolinone Recrystallize in ethanol.

  Yield: 93% Melting point: 105-106 ° C

  EXAMPLE 5 PROPYL-6 BENZOTHIAZOLINONE

  Proceed in the same way as in example 1, replacing the

  benzoyl-6 benzothiazolinone by propionyl-6 benzothiazolinone.

  EXAMPLE 6 3-METHYL-6-PROPYL BENZOTHIAZOLINONE

  Proceed in the same way as in example 1, replacing the

  benzoyl-6 benzothiazolinone by 3-methyl-6-propionyl benzothiazolinone.

  EXAMPLE 7 BUTYL-6 BENZOTHIAZOLINONE

  Proceed in the same way as in example 1, replacing the

  benzoyl-6 benzothiazolinone with butyryl-6 benzothiazolinone.

  Recrystallize in acetonitrile.

  Yield: 93% Melting Point: 127-129 C Spectral Characteristics: 1 H NMR 0.95 ppm Triplet, 3 H, CH 3 Solvent: CD C 13

  EXAMPLE 8 METHYL-3-BUTYL-6 BENZOTHIAZOLINONE

  Proceed in the same way as in example 1, replacing the

  benzoyl-6 benzothiazolinone by 3-methyl-6-butyrylbenzothiazolinone.

  EXAMPLE 9 PENTYL-6 BENZOTHIAZOLINONE

  Proceed in the same way as in example 1, replacing the

  benzoyl-6 benzothiazolinone with 6-valeryl benzothiazolinone.

  Recrystallize in cyclohexane.

  Yield: 92% Melting point: 80-81 C

  EXAMPLE 10 METHYL-3-PENTYL-6 BENZOTHIAZOLINONE

  Proceed in the same way as in example 1, replacing the

  benzoyl-6 benzothiazolinone with 3-methyl-6-valeryl benzothiazolinone.

EXAMPLE 11

  (THIENYL-2 METHYL) -6 BENZOTHIAZOLINONE

  Proceed in the same way as in example 1, replacing the

  benzoyl-6 benzothiazolinone by (thenoyl-2) -6 benzothiazolinone.

  EXAMPLE 12 METHYL-3 (THIENYL-2-METHYL) -6-BENZOTHIAZOLINONE

  Proceed in the same manner as in Example 1, replacing the 6-benzoyl benzothiazolinone by methyl-3 (thenoyl-2) -6 benzothiazolinone. -9

  EXAMPLE 13 (HYDROXY-4-BUTYL) -6 BENZOTHIAZOLINONE

  Proceed in the same way as in example 1, replacing the

  benzoyl-6 benzothiazolinone with (4-hydroxy-butyryl) -6 benzothiazolinone.

  EXAMPLE 14: METHYL-3 (HYDROXY-4-BUTYL) -6 BENZOTHIAZOLINONE

  Proceed in the same manner as in Example 13, replacing (6-hydroxy-4-butyryl) benzothiazolinone with methyl-3 (4-hydroxy)

butyryl) -6 benzothiazolinone.

  EXAMPLE 15 3-METHYL ETHYL-6 BENZOTHIAZOLINONE

  Proceed in the same way as in example 1, replacing the

  benzoyl-6 benzothiazolinone by 3-methyl-6-acetyl benzothiazolinone.

  EXAMPLE 16: METHYL-3 (BROMO-2 ETHYL) -6 BENZOTHIAZOLINONE

  Proceed in the same manner as in Example 1, replacing the 6-benzoyl benzothiazolinone by methyl-3 (bromoacetyl) -6

  benzothiazolinone Recrystallize from cyclohexane.

  Yield: 86% Melting point: 97-98 ° C

  EXAMPLE 17 (6-CHLORO-PROPYL) BENZOTHIAZOLINONE

  Proceed in the same manner as in Example 1, replacing the 6-benzoyl benzothiazolinone by (3-chloro-propionyl) -6

  benzothiazolinone Recrystallize in toluene.

  Yield: 86% Melting point: 41-43 C -10-

  EXAMPLE 18: METHYL-3 (3-CHLORO-PROPYL) -6 BENZOTHIAZOLINONE

  Proceed in the same manner as in Example 1, replacing the 6-benzoyl benzothiazolinone by methyl-3 (3-chloro-propionyl) -6

  benzothiazolinone Recrystallize from cyclohexane.

  Yield: 84% Melting point: 41-43 ° C

  EXAMPLE 19 (CYANO-3 PROPYL) -6 BENZOTHIAZOLINONE

  Dissolve 0.01 mole of (3-chloro-propyl) benzothiazolinone obtained in Example 19 in 100 cm 3 of dimethyl formamide Add 0.01 mole of CN Cu, 0.01 mole of CN Na and 0.02 mole of KCN and stir overnight Evaporate the medium to dryness under reduced pressure Dissolve the residue in chloroform and wash with water several times Dry phase

  Organic Evaporate to dry Recrystallize the residue.

  EXAMPLE 20 (CARBOXY-3 PROPYL) -6 BENZOTHIAZOLINONE

  Place 0.01 mole of (3- (cyano-3-propyl) benzothiazolinone in 50 ml of diluted hydrochloric acid at reflux.

  cooling with chloroform Dry over sodium sulfate.

  Evaporate the organic phase Recrystallize.

  EXAMPLE 21: METHYL-3 (CYANO-3-PROPYL) -6-BENZOTHIAZOLINONE

  Proceed as in Example 21, replacing (3-chloropropyl) -

  6 benzothiazolinone by methyl-3 (3-chloro-propyl) -6 benzothiazolinone

obtained in Example 20.

  EXAMPLE 22 BENZYL-6 BENZOTHIAZOLINONE, DIETHANOLANINE SALT

  In a 250 cm 3 flask, dissolve 0.04 mole of benzyl-6-benzothiazolinone in 150 cm 3 of dioxane. Add dropwise 0.04 mole of diethanolanine with magnetic stirring.

  two hours Spin, dry and recrystallize.

-11-

  EXAMPLE 23 (6-PHENYL ETHYL) BENZOTHIAZOLINONE

  Proceed as in Example 1, replacing benzoyl-6

  benzothiazolinone with 6-phenylacetyl benzothiazolinone.

  EXAMPLE 24: (4-METHYL-PHENYL) -6-METHYL-BENZOTHIAZOLINONE Proceed as in Example 1, replacing benzoyl-6

  benzothiazolinone with p-6-toluoyl benzothiazolinone.

  EXAMPLE 25 (TRIFLUOROMETHYL-4-PHENYL) METHYL-6

benzothiazolinone

  Proceed as in Example 1, replacing benzoyl-6

  benzothiazolinone by (4-trifluoromethylbenzoyl) -6 benzothiazolinone.

  EXAMPLE 26 P ANISYL-6 BENZOTHIAZOLINONE

  Proceed as in Example 1, replacing benzoyl-6

  benzothiazolinone with 6-anisoyl benzothiazolinone.

Melting point: 181,182 ° C

  EXAMPLE 27 (FURYL-2-METHYL) -6 BENZOTHIAZOLINONE

  Proceed in the same way as in example 1, replacing the

  benzoyl-6 benzothiazolinone by la (furoyl-2) -6 benzothiazolinone.

  EXAMPLE 28 1- (3,5-DICHLORO-PHENYL) -6-METHYL-BENZOTHIAZOLINONE Proceed in the same manner as in Example 1, replacing the 6-benzoyl-benzothiazolinone with (3,5-dichlorobenzoyl) -6-benzothiazolinone. EXAMPLE 29: 1- (TRIMETHOXY-3,4,5-PHENYL) -6-METHYL-BENZOTHIAZOLINONE Proceed in the same manner as in Example 1, replacing benzoyl-6-benzothiazolinone with (3,4,5-trimethoxybenzoyl) 6 benzothiazolinone.

  PHARMACOLOGICAL STUDY OF THE DERIVATIVES OF THE INVENTION

  EXAMPLE 30: STUDY OF ACUTE TOXICITY

  Acute toxicity was assessed after oral administration to 5 mice (20 + 2 grams) of increasing doses (0.1 0.25 0.50 -0.75 1 g / kg) Animals were observed at intervals regular at O 10 during the first day and daily during the 2 weeks

following the treatment.

  It appears that the compounds of the invention are completely non-toxic No death is observed after administration of a dose 1 g kg-1 No disorders are observed after administration of this

dose.

  EXAMPLE 31: STUDY OF THE ANALGESIC ACTIVITY

  The activity on pain was investigated in mice (20-25 g) according to a protocol derived from the technique described by SIEGMUND (SIEGMUND EA, RA, CADMUS & GOLU, J Pharm Exp Ther 119, 1874, 1954). , randomly allocated in batches of 12 animals, received oral treatment (excipient for controls) 1 hour before

  intraperitoneal injection of a hydroalcoholic solution of phenyl-p-

  Benzoquinone (Sigma) at 0.02% Stretches are counted between the 5 th

  and 10th minute after the injection.

  The percentage of activity obtained was evaluated for each dose (% decrease in the number of stretches in the treated patients compared to the controls). An ED 50, dose resulting in an activity of 50%, was determined

for each product.

  It has been found that certain compounds of the invention possess a very interesting analgesic activity. Thus, the ED 50 of the compound of

  Example 1 is close to 2 mg kg-1.

  By way of comparison, the administration of a dose of 100 mg kg-1 of the derivatives of patent FR 73 23280 caused a percentage of analgesia - in a comparable test of the order of 25 to 60% and the compound of the French patent. 80 20861, whose analgesic activity is the most interesting, had in the same Siegmund test an ED 50 of 9 mg kg-1, ie approximately 4.5 times greater than that of the most interesting product of the present invention.

invention.

  EXAMPLE 32 STUDY OF ANTI-INFLAMMATORY ACTIVITY

  The anti-inflammatory potential of the compounds was investigated on a model of acute inflammation caused by subcutaneous injection of a carrageenin solution at the posterior rat paw, according to a technique inspired by the WINTERCH method; EA RISLEY, GN NUSS (Proc Soc Exp Med 111, 554, 1962) The rats (100-120 g), randomized in batches of 8, were treated (including the controls which receive the excipient) 1 hour before the local injection of a 0.5% carrageenan suspension (type IV, Sigma, 0.1 ml of rat) The edema is determined 3 hours after the injection, by plethysmometric measurement (water plethysmometer UGO BASIL) of the volume of each of the hind legs (edema = volume of the inflamed paw minus the volume of the paw not inflamed). It appears that the products of the invention have no activity on this test In comparison, the products of patent FR 73 23280 possess

an anti-inflammatory activity.

-14-

  EXAMPLE 33: PHARMACEUTICAL COMPOSITION: TABLETS

  Tablets dosed with 20 mg benzyl benzothiazolinone,

  Preparation formula for 1000 tablets.

  Benzyl-6 benzothiazolinone 20 g Wheat starch 15 g Maize starch 15 g Lactose 65 g Magnesium stearate 2 g Silica 1 g Hydroxypropylcellulose 2 g -15-

Claims (9)

1 / Compounds of general formula (I): wherein R1 represents a hydrogen atom or a lower alkyl group, R 2 represents: a linear lower alkyl group or optionally substituted with one or more of halogen or with one or more hydroxy, phenyl, carboxylic acid, or cyano, branched alkoxy groups, with the proviso that if R 1 represents a hydrogen atom, then R 2 may not represent a group methyl, a methyl group substituted with a halogen atom, an aryl group optionally substituted with one or more halogen atoms, or cyano groups, lower alkyl groups optionally substituted by one or more halogen atoms, or alkoxy groups; lower, or carboxylic acid or hydroxy, a heteroaryl group preferably 2-thienyl, 2-furyl optionally substituted by a lower alkyl group lin area or branched, the lower term indicating that the groups thus qualified have 1 to 6 carbon atoms, their enantiomers, diastereoisomers and epimers and, when R 1 represents a hydrogen atom or R 2 comprises a carboxylic acid group their salts are addition to a pharmaceutically acceptable base.   2 / Compounds according to claim 1, wherein R 2 is an aryl group and when R 1 is a hydrogen atom   their addition salts to a pharmaceutically acceptable base.   3 / Compounds according to claim 1, wherein R1 represents a hydrogen atom their isomers as well as their addition salts at a pharmaceutically acceptable base.   4 / Compounds according to claim 1, wherein R1 represents a methyl group and their isomers and when R 2 comprises a carboxylic acid group their addition salts with a base pharmaceutically acceptable.   5 / Compounds according to claim 1 which is benzyl-6-benzothiazolinone and the addition salts with a base pharmaceutically acceptable.   6 / Compounds according to claim 1, in which R 2 represents a linear or branched lower alkyl group substituted with a carboxyl group, as well as their isomers and their addition salts with   a pharmaceutically acceptable base.   7 / compounds according to claim 1 wherein R 2 represents a linear or branched lower alkyl group substituted by a halogen atom and different from halo methyl and their isomers and 17 - when R1 represents a hydrogen atom, their salts addition to a pharmaceutically acceptable base.   8 / compounds according to claim 1 wherein R 2 represents an aryl group substituted by a lower alkyl group or by one or more halogen atoms or by a trifluoromethyl group and when R 1 represents a hydrogen atom, their salts of addition to   a pharmaceutically acceptable base.   9 / Process for the preparation of the compounds of general formula (I), according to claim 1, characterized in that a derivative of formula (II) is used as starting material: (II) ol -R 2 o in which R 1 and R 2 have the same meaning as in formula (I), which, in an acid medium, are reduced by a trialkylsilane to conduct after purification by a technique chosen from washing, chromatography and / or crystallizations with the product of formula (I): (I) CH 2 R 2   in which R 1 and R 2 have the same meaning as in formula (I), II which when R 2 comprises a cyano group can be converted into a derivative of formula (I) in which R 2 comprises a carboxylic group per action on the derivative of formula (I / A) previously obtained from a strong acid, which when R 2 comprises a halogen atom can be treated with an alkali metal cyanide to give a derivative of formula (I / A) in which R 2 comprises a cyano group, which cyano group can be converted into a carboxyl group as indicated above to give a derivative of formula (I) in which R 2 comprises a carboxylic acid group, the isomers of which are optionally separated by a conventional separation technique and that is salified, if desired, when R1 represents a hydrogen atom or when R 2 comprises a carboxylic acid group with a pharmaceutically acceptable base or when R 2 comprises nd a   amino group with a pharmaceutically acceptable acid.   Pharmaceutical composition containing as active ingredient   less a compound according to one of claims 1 to 8 in combination with   one or more inert, non-toxic excipients or vehicles, pharmaceutically acceptable.   11 / The pharmaceutical composition according to claim 10 containing   at least one active principle according to one of claims 1 to 8 usable   as an analgesic as well as in the prevention of arterial accidents.